Metabolic syndrome score and cardiovascular disease risk in adults with cardiovascular-kidney-metabolic syndrome stages 0–3: A prospective cohort study

Background: The American Heart Association (AHA) introduced the Cardiovascular-Kidney-Metabolic (CKM) syndrome framework, emphasizing the interplay of metabolic risk factors, chronic kidney disease, and cardiovascular disease (CVD). Whether the metabolic syndrome (MetS) score-a simple count of metabolic abnormalities-provides additional risk information within CKM stages 0-3 remains uncertain. This study examined the association between MetS score and incident CVD in a CHARLS-based cohort with CKM stages 0-3. Methods: We analyzed 7889 participants aged ≥45 years from the China Health and Retirement Longitudinal Study (CHARLS) with CKM stages 0-3 and no baseline CVD. CKM staging was corrected to enforce hierarchical consistency (participants with ≥2 MetS components were classified as at least Stage 2). MetS score (0-5) was defined per harmonized criteria. The primary outcome was incident CVD (self-reported heart disease or stroke) over 7-year follow-up. Cox proportional hazards models (with CKM stage in the primary model, without adjusting for MetS components), restricted cubic spline analyses, Modified Poisson regression, subgroup analyses, and sensitivity analyses were performed. Single iterative imputation addressed missing covariates (<3% per variable). Results: During median 7.0-year follow-up, 815 participants (10.3%) developed CVD. After full adjustment including CKM stage, each 1-point higher MetS score was associated with 22.3% higher CVD risk (HR: 1.223, 95% CI: 1.143-1.308, P < 0.001). The highest quartile had over twice the risk of the lowest (HR: 2.206, 95% CI: 1.625-2.996, P < 0.001; P for trend < 0.001). A categorical dose-response was confirmed (score 5 vs. 0: HR 3.379). The association was stronger for stroke (HR: 1.333) than heart disease (HR: 1.119; P for heterogeneity = 0.009). Adding MetS score to CKM stage significantly improved model fit (likelihood-ratio P < 0.001) but yielded modest discrimination improvement (ΔC-statistic: 0.017, 95% CI: 0.006-0.029). Results were robust across sensitivity analyses. Conclusions: In this CHARLS-based cohort of Chinese adults with CKM stages 0-3, a higher MetS score was independently associated with elevated CVD risk in a graded, dose-response manner. The MetS score captures cumulative metabolic burden beyond CKM staging, though its incremental discriminative value is modest. Further validation with adjudicated outcomes and accurate event timing is warranted.